Short bowel syndrome (SBS) following massive small bowel resection (SBR) is a major cause of intestinal failure in adults and children, with a high rate of morbidity and mortality and enormous health care-related costs. Patients with SBS often require parenteral nutrition (PN) due to chronic malabsorption and malnutrition and commonly develop infection from gut-derived bacteria, suggesting a decrease in gut barrier function. In animal models of SBS, marked gut mucosal growth and improved nutrient transport function occur over time (intestinal adaptation). Although SBS patients commonly exhibit decreased diet-induced diarrhea within the first 2 years after SBR, very little clinical investigation on possible early adaptive changes in small bowel or colonic mucosal growth indices, nutrient absorption or gut barrier function has been performed over time. In the P.l.'s ongoing blinded study of diet +/- growth hormone in adults with chronic SBS, nitrogen, fluid and electrolyte absorption is improved and PN needs markedly decreased, without an apparent change in gut mucosal growth. The patients also demonstrate up-regulated expression of the di/tripeptide transporter PepT1 in colonic mucosa versus controls, suggesting a functional mechanism for endogenous gut adaptation. Our data also show markedly increased IgA and IgG antibody titers to bacterial flagellin in SBS and suggest that plasma citrulline may be a useful biomarker of functional enterocyte mass. The proposed pilot study will be the first comprehensive investigation of serial changes in gut mucosal structure and function in the early period (2-30 months) of SBS in adults. Our Specific Aims are: 1) To determine after massive SBR whether the residual small bowel and colonic mucosa exhibits adaptive growth, with concomitantly improved nutrient absorption and gut barrier function; 2) To determine potential mechanisms of early gut adaptation in human SBS, by evaluating changes in mucosal cell proliferation and apoptosis and expression of key molecules known to regulate nutrient transport/absorption and gut barrier function; and 3) To evaluate the utility of plasma citrulline concentrations and serum flagellin antibody titers as biomarkers for human enterocyte absorptive capacity and gut barrier function, respectively. Our research will provide important and novel information on the natural history and underlying mechanisms of early intestinal adaptation in man that should guide future therapeutic trials in patients with SBS-induced gut failure.